Living biological metabolism has traditionally been studied by chemical analysis of tissue samples removed from living tissue or organism. In the process, the tissue examined loses viability in its original form and function.
Developments in radiography during this century have led to analysis of metabolic activity based on the external application of ionizing radiation. In this approach, living tissue exhibits characteristic attenuation of the energy applied. Attenuation differences between adjacent tissues can be reflected by different exposure intensities of film. Alternative approaches include internal application of ionizing radiation, typically by injection of radioisotopes into the circulation, with image production resulting from anatomic distribution and concentration of radioactivity. Both approaches have been prevalent in medicine since early this century.
In the mid-1940's, the physical phenomenon of nuclear magnetism was discovered. Initially, the phenomenon was used to study chemical constructs in relatively pure forms, with the most actively studied isotope being 'H (Proton). Toward the 1960's, the lessons of nuclear magnetic spectroscopy were increasingly applied to complex chemical compositions, such as living biological macromolecules, and ultimately living biological tissues, such as cell water. The field expanded to include medically relevant applications when, in 1971, R. Damadian reported in Science (171:1151-53, 1971) his ability to detect tumors by measurement of different proton resonance in cell water derived from tumors.
During the years since 1971, study of living biological magnetic resonance has been used to create both numerical representation of isotopes (Magnetic Resonance Spectroscopy; MRS) as well as graphic images of their location and metabolic characteristics within living tissue. The latter technology has been adapted by the world of medicine and applied in a manner known as Magnetic Resonance Imaging (MRI). MRI has been found to offer advantages over other diagnostic modalities in selected cases, such as the diagnosis of pheochromocytoma and diseases of the central nervous system. MRI is generally considered harmless at current configurations because of the low intensity magnetic radiation utilized to cause the nuclei to emit a resonance signal. Despite this attribute, it has yet to supplant Computerized Axial Tomography (CAT) scanning, which gives generally similar anatomical images, but whose application is limited by the risks of ionizing radiation and the frequent need for adjunctive toxic contrast media. The reasons undoubtedly include cost, but also the absence of multiple clearly demonstrable advantages over other existing techniques, such as CAT scanning. Improvements in the diagnostic capabilities of MRI would be welcome in the study of biology in general, but especially in the world of medicine, where concern for human health limits the use of other diagnostic methods such as cat scanning which may have an unacceptably high risk/benefit ratio for the particular diagnostic procedure.
The types of atoms having naturally occurring magnetic isotopes is large but is not unlimited. Further, the relative proportion of any specific magnetic isotope of a given atom is frequently very low (Ex., C. S. Springer, Jr. "Measurement of Metal Cation Compartmentalization In Tissue By High-Resolution Metal Cation NMR", Ann Rev Biophys Chem 16:375-99, 1987). Thus, the application of medical MRI has focused on the most abundant magnetic nucleus in living biological tissues, .sup.1 H, because of its prevalence in nature and because of the relative scarcity of other magnetic isotopes Ex., R. L. Nunnally and PR Antich, "New Directions in Medical Imaging of Cancer" (Cancer 67:1271-1277, 1991). Attempts have also been made to utilize other naturally occurring magnetic nuclei, such as .sup.13 C, .sup.19 F, .sup.23 Na, and .sup.31 P. As for example disclosed in U.S. Pat. No. 4,779,619 where .sup.23 Na is used for brain function analysis. Also, for example, H. Kantor et al, "In Vivo .sup.31 P Nuclear Magnetic Resonance Measurements in Canine Heart Using a Catheter-Coil" (Circ Res 55:261-266, 1984), disclose the use of .sup.31 P for heart function analysis in canines; and I. R. Francis et al, "Malignant Hepatic Tumors: P-31 MR Spectroscopy with One-dimensional Chemical Shift Imaging" (Radiology 180:341-344 1991), disclose use of naturally occurring .sup.31 P for liver tumor detection.
In an effort to improve resonance detection, technical innovations have been applied to MRI machinery. Many imaging modalities have been introduced since Lauterbur introduced the concept of "zeugmatography". Hardware configuration has evolved to include a variety of magnets to alternatively establish and remove magnetic fields so nuclear magnetic resonance is generated. Advances in antenna design for detecting the resonance frequencies of various nuclei include surface applied or internally applied coils, with easily interchangeable frequency sensitivities. For example, U.S. Pat. No. 4,672,972 discloses a solid state NMR probe which both receives a resonance on or from proximate tissue and modulates a magnetic field in the proximity of the tissue from which resonance signal is detected.
Attempts have also been made to alter the physical environment within the tissue. One method causes induction of normal metabolic cascades known to alter the spin states of the magnetic nucleus. Thus, for example, fructose causes reduction of MRI-detectable inorganic liver phosphate, and allows a dynamic assessment of liver function through .sup.37 P spectroscopy (F. Terrier et al, Radiology 171:557-563 1989).
Other approaches, as disclosed in U.S. Pat. Nos. 4,532,217; 4,731,239; 4,735,796; 4,849,210; and 4,985,233 include the use or administration of paramagnetic, diamagnetic, and ferromagnetic contrast enhancement particles or agents, which agents may or may not be metabolized by the tissue; but, which agents normally have little if anything to do with the metabolic activity of the tissue in question. Essentially a contrast between areas in which signals are generated by the isotope and those where they are not generated is enhanced to create a greater "shadow" for imaging purposes. Such contrast agents, for example, may cause reduction of relaxation times of an endogenous (i.e. unadministered) nucleus under study and improve signal/noise ratios. Alternatively, as for example with metabolizable ferromagnetic particles such as iron dextran particles, the contrast agents may focus and concentrate the magnetic field. Contrast agents, such a those described in the patents listed above, specifically do not contain MRI-sensitive nuclei. By definition, such contrast enhancers are not detected directly on images and spectra; they are not generating the resonance frequency signal, but rather they act to alter the magnetic environment of an endogenous isotope under analysis.
To a limited extent, chemists have previously applied increased concentrations of various magnetic isotopes to proteins and enzymes and other non-living macromolecules for NMR studies. Pharmacologist have even used naturally abundant, i.e. unenriched, magnetic isotopes to label drugs for the study of drug metabolism and distribution, in living organisms. There are recommendations in the literature, however, to avoid the use of most magnetic isotopes as their concentrations are low enough as to render them useless under current configurations and applications (Ex., Crooks et al., "Tomography of hydrogen with nuclear magnetic resonance (NMR) and the potential for imaging other body constituents" SPIE 206:120-128, 1979). In part because of the emphasis on NMR studies of naturally abundant magnetic isotopes and in part because of such recommendations most magnetic isotopes have been ignored; exogenous administration of concentrated magnetic isotopes for the study of living biological tissue has not been discovered.
Prostatic cancer has been studied with .sup.1 H MRI. The resolution of the MRI images has been limited and improved contrast agent methodologies as well as improved probes have been developed to address this limitation. Prostatic zinc metabolism has separately been studied using various radioactive Zn isotopes, such as .sup.65 Zn and .sup.69 Zn, administered to test subjects. The rapid uptake of Zn by the prostate and discrepancies between Zn metabolism and distribution in healthy and diseased prostates have been observed. These observations have not previously led to the concept of .sup.67 Zn prostatic MRI. The low natural concentration of .sup.67 Zn would result in poor resolution. Prior to the present invention, despite the need for better testing modalities, increasing the concentration of non-radioactive magnetic .sup.67 Zn was not disclosed, suggested or implemented.